The present invention relates to theobromine with an anti-carcinogenic activity, and more particularly, to theobromine which inhibits the suppression of gap junctional intercellular communication (GJIC), a pathological phenomenon occurring during development of various kinds of cancers including liver cancer, as well as DNA synthesis of cancer cells thereby inhibiting proliferation of cancer cells.
Although a wide range of attempts has been made to treat cancer over the last three decades, incidence and death rates of cancer have not decreased. (Sporn, M. B., Lancet, 347:1377-1381, 1996) This appears mainly due to the fact that the approaches on cancers for the past thirty years have been mostly focused on from the therapeutic point rather than preventive point. As is already known, intake of certain food or a drug that contains components which can effectively inhibit or delay the multi-step progress of cancer will help to reduce the risk of cancer and the subsequent mortalities resulted thereof and many researches have been carried out (Kang et al., Chemoprevention of cancer, Korea Medicine, 2000; Surh, Y. J., Mutat. Res, 428:305-327, 1999; Sporn, M. B., Lancet, 347:1377-1381, 1996; Caragay, A. B., Food Technol., 65-68, 1992).
Carcinogenesis is a multi-step process comprising stages of initiation, promotion and progression. In searching of agents which may be effective in prevention or inhibition of cancer, the recent researches have been more concerned with identifying substances that can inhibit promotion and promotion stages rather than those of initiation stage, which is a relatively short and irreversible stage (Kang et al., Chemoprevention of cancer, Korea Medicine, 2000; Surh, Y. J., Mutat. Res, 428: 305-327, 1999; Sporn, M. B., Lancet, 347: 1377-1381, 1996). In particular, unlike pharmaceutical drugs, the prevention and inhibition of cancer by means of food extract and fraction will become more effective if they target on the promotion stage of carcinogenesis, which is generally progressed for more than 20 years and is also reversible (Kang et al., Chemoprevention of cancer, Korea Medicine, 135-136, 2000; Yamasaki, H. et al, Carcinogenesis 11: 1051-1058, 1999; Kelloff. G. J. et al., Eur. J. Cancer, 35: 1755-1762, 1999; Surh, Y. J., Mutat. Res, 428: 305-327, 1999).
Gap junctional intercellular communication (GJIC) is essential for maintaining the homeostatic balance through modulating cell proliferation and differentiation in multicellular organisms. Inhibition of GJIC is considered as a key biochemical index observed at carcinogenesis, particularly to tumor promotion stage; therefore, substances that can inhibit such a process is expected to inhibit the promotion stage of carcinogenesis thereby preventing as well as inhibiting the development of cancer. Further, proliferation of cancer cells by DNA synthesis is considered as a key biological index observed at the progression stage of carcinogenesis; therefore, substances that can inhibit such a process is expected to inhibit the progression stage of carcinogenesis thereby preventing as well as inhibiting the development of cancer (Kang et al., Chemoprevention of cancer, Korea Medicine, 135-136, 2000; Yamasaki, H. et al, Carcinogenesis 11:1051-1058, 1990; Kelloff. G. J. et al., Eur. J. Cancer, 35:1755-1762, 1999; Surh, Y. J., Mutat. Res, 428: 305-327, 1999; Holder. J. W. et al., Cancer Res., 53:3475-3485, 1993).
A variety of foods such as coffee, tea, coke and chocolate contain caffeine, a xanthine derivative (Lee, W. J., Pharmacology Lecture, Medical culture, 195-198, 1993). In particular, theobromine, also a xanthine derivative, is abundant in cacao bean or cacao bean husk unlike caffeine. In general, cacao bean contains about 1.5-3% of theobromine and cacao bean husk contains about 2% of theobromine. Processed food such as chocolate, which is made from cacao bean, contains about 0.2-0.5% of theobromine and this content is about 7-10 times larger than that of caffeine (Barry, L. Z. et al., J. Food Sci., 45:314-316, 1980). General pharmacological functions of xanthine derivatives are stimulation of central nervous system, skeletal muscle and cardiac muscle as well as relaxation of smooth muscle and coronary artery, accentuation of secretion of gastric juice, and diuresis. However, the pharmacological activity of theobromine is known to be much weaker than that of caffeine (Lee, W. J., Pharmacology Lecture, Medical culture, 195-198, 1993). By contrast, caffeine is present in a variety of foods and has a wide scope of pharmacological activities, theobromine is only abundantly present in cacao bean and cacao bean husk and thus the studies on theobromine has not been extensively carried out. Caffeine has been reported to have an anti-carcinogenic activities; for example, a synergistic effect on therapeutic agent for gastric cancer (Takahashi, M. et al., Anticancer Res. 18:4399-4402, 1998), an inhibitory effect on lung cancer (Jeffrey, C. et al., Cancer Res. 38:1757-1761, 1978; Chung, F. L. et al., Cancer Res., 58:4096-4101, 1998), and an inhibitory effect on TPA (12-O-tetradecanoyphorbol-13-acetate)-induced carcinogenesis (Perchellet, J. P. et al., Cancer Res. 41:3927-3925, 1981). In the preventive role of green tea and black tea, caffeine has been also reported to play an important role in parallel with polyphenol (Yang. C. S., Biofactor 13:73-79, 1999; Huang, M. T. et al., Cancer Res. 57: 2623-2629, 1997; Lu, Y. P. et al., Cancer Res., 61: 5002-5009, 2001).
However, there have been no studies revealed on the effect of theobromine contained in cacao bean and cacao bean husk with respect to prevention and inhibition of cancers. In particular, there has been no report on the effect of theobromine on cancers the developmental rates of which are relatively high in Asians as well as Koreans such as liver cancer, gastric cancer and colon cancer.
The inventors of the present invention, while searching for a promising candidate for an anti-carcinogenic agent among natural foods for safety reason, discovered that theobromine, which is abundantly present in cacao bean and cacao bean husk, has an anti-carcinogenic activity such as inhibiting the suppression of GJIC and DNA synthesis of cancer cells, which are characteristic pathological phenomena occurring during promotion and progression stages of carcinogenesis.
Therefore, the object of the present invention is to provide an anti-carcinogenic agent comprising theobromine as an active ingredient.